In-line IV drug delivery pack with controllable dilution

ABSTRACT

An in-line drug delivery pack that connects in-line with an intravenous (IV) line and allows for the mixing of diluent with a drug reagent to be delivered to the patient. An internal drug bed bypass mechanism is tailored to apportion diluent flow between the bypass and the drug bed. The apportionment is selected to achieve a solution concentration suitable for IV administration as the dried reagent is dissolved. Thus, both dissolution and precisely tailored dilution are performed in the same simple device.

REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.10/214,558, filed Aug. 6, 2002 now U.S. Pat. No. 6,520,932, which is acontinuation of U.S. patent application Ser. No. 09/717,796, filed Nov.20, 2000 now U.S. Pat. No. 6,428,505, which claims the benefit ofpriority to U.S. provisional application No. 60/166,597, filed Nov. 19,1999, all of which are hereby incorporated by reference in theirentirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to drug delivery devices, andmore particularly to devices for storing, transporting and dissolvingdry reagents.

2. Description of the Related Art

Medical treatments often involve solutions or suspensions of drugs orother reagents to be injected into the human body. Mixing and injectingsuch solutions can be extremely expensive and inaccurate. Thus, thereare a number of problems with current methods of intravenous drugdelivery.

Conventional methods involve administration of drug solutions derivedfrom thawed preparations of previously frozen drug solutions or fromdrug solutions produced by connection of a diluent pouch with adrug-containing vial. The later delivery method requires considerablemanipulation to place the dry drug formulation into solution prior toadministration to the patient. Among the greatest problems associatedwith existing methods are the direct and indirect costs of the deliverysystems. For frozen solutions indirect costs are associated withfreezers, temperature monitoring equipment and procedures required tomaintain drug supplies. Direct costs are associated with the laborrequired to thaw the frozen solutions prior to administration to thepatient. Similarly, for preparation of drug solutions using dry drug andseparate diluent preparations, costs are associated with the requirementfor multiple components and the manipulation required to place the drugin solution.

The requirement for freezing drug solutions or use of multiplecomponents to prepare drug solutions results from the instability ofmany drugs once the drugs are activated or placed into solution. Overtime, sometimes within a matter of 1 to 2 hours, the efficacy of drugsdiminishes after they are placed in solution. Accordingly, additionalcosts are associated with the waste associated with formation of drugsolutions that are not administered to the patient in a timely manner,for example, when changes in prescription or patient movement precludeadministration of the prepared drug solution.

The manipulation associated with combining a separate drug vial and adiluent from a pouch includes threading of a separate drug-containingvial into a threaded receptacle. Inadequate threading together of thesecomponents results in leakage of the diluent or drug solution from thisjunction and breaches the sterile barrier intended to be formed betweenthe drug vial and the diluent pouch. The repeated effort required tothread these separate components together has lead to carpal tunnelsyndrome among healthcare providers. For certain delivery systems, aninternal cork must be removed by manipulation through the walls for thediluent pouch in order to expose the dry drug within the vial to thediluent. Omission of this step results in administration of diluentwithout drug to the patient.

Moreover, in order to properly dissolve the drug in the diluent thecombination of components must be vigorously agitated. It is often notpossible to be absolutely certain that all the drug has been removedfrom the vial. Because of the translucent nature of the diluent pouch,it is also sometimes difficult to differentiate between dissolved drugand minute, undissolved drug particles within the diluent pouch. Ifundissolved drug particles are administered to patients they present aserious potential hazard to the patient of an embolus capable ofoccluding small blood vessels.

Administration of the additional fluids required for administration ofdrug solutions using a secondary set of fluids, beyond thoseadministered to maintain electrolyte balance, results in fluid problemsin patients with fluid retention maladies.

The volume occupied by existing delivery systems and/or the requirementfor maintaining a frozen environment prevents these systems from beingused in automated dispensing devices.

An alternative to use of these delivery systems is the preparation ofdrug solutions by pharmaceutical personnel from bulk containers of drug.These procedures require a considerable amount of effort by thesepersonnel and represents a serious hazard to the pharmacy and drugadministration personnel due to the toxicity of some agents.

U.S. Pat. No. 5,259,954 to Taylor, issued Nov. 9, 1993 (hereinafter “the'954 patent”) and U.S. Pat. No. 5,725,777 issued Mar. 10, 1998(hereinafter “the '777 patent”) disclose a drug pack or “reagent module”suitable for storing dry reagents and for preparing solutions foradministration by passing fluid through the pack. These references areincorporated herein by reference. The '777 patent discloses twoembodiments in which a porous compression element constantly exerts aninward force on a dry reagent bed, keeping it compacted even as the bedis eroded by passing fluid through the porous compression element andthrough the bed. This arrangement advantageously enables efficientuniform dissolution of the reagent bed by avoiding channel formationthrough the reagent bed.

While the reagent modules of the '954 and '777 patents operate well instoring and dissolving reagent beds efficiently, there remains room forimprovement.

SUMMARY OF THE INVENTION

An in-line drug delivery pack that connects in-line with an intravenous(IV) line and allows for the mixing of diluent with a drug reagent to bedelivered to the patient. An internal drug bed bypass mechanism istailored to apportion diluent flow between the bypass and the drug bed.The apportionment is selected to achieve a solution concentrationsuitable for IV administration as the dried reagent is dissolved.

Thus, both dissolution and precisely tailored dilution are performed inthe same simple device.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an elevational view of an IV line drug delivery system, with ajoint connecting a diluent line and a concentrated solution drip.

FIG. 2 is an elevational view of an in-line IV drug delivery system,constructed in accordance with a preferred embodiment of the presentinvention.

FIG. 3 is an elevational cross-section of a drug delivery pack for usein-line along an IV line.

FIG. 4 is a sectional view taken along lines 4—4 in FIG. 3.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Description of Components

One drug delivery system is shown in FIG. 1. The intravenous bag 1 isconnected to a drug delivery bag 5 by means of a Y-connector 20. TheY-connector 20 combines the solutions into an injection line 25 that issubsequently introduced to the hand 30 or any other body part. The drugdelivery bag 5 holds pre-formed concentrated solution, which is dilutedfor IV injection by fluid from the diluent bag 1. As noted in theBackground section, this arrangement has certain disadvantages.

With reference to FIG. 2, a drug delivery pack 35 is shown in-line withan intravenous solution bag 1. The solution bag 1 is part of theintravenous delivery system 36. The IV line 3 leads from the intravenousdelivery system 36 to the drug delivery pack 35 via Luer locks 4, andthen to an injection site 30, which in this example is at a human hand.Those skilled in the art will realize that other injection sites includebut are not limited to the arm, neck and leg.

Now referring to FIG. 3, a housing 37 of the drug delivery pack 35 ispreferably composed of a clear material, such as plastic polymer orglass. An inlet 40 in the housing top 45 provides a connection betweenan input line (not shown), such as an IV line, and the body of thehousing 37. The inlet 40 includes a collar 42 terminating at one endwith a connection fitting 55 to connect to the diluent source. Thehousing 37 also contains an air vent (not shown) and a terminal outlet160 at the axial terminus of the housing 37 opposite to the inlet 40.The air vent is preferably sealed against fluid flow by an airpermeable/fluid impermeable barrier or a mechanical valve.

Immediately adjacent to the inlet 40 is a distribution chamber 60,defined between an inlet frit 80 and the housing top 45, which areseparated by radial fins 65 protruding from the housing top 45.Referring to FIG. 4, the radial fins 65 are shown in a cross-section,stopping short of a central opening.

Referring again to FIG. 3, the inlet frit 80 is a porous material, whichcan be hydrophilic but is preferably hydrophobic. The porosity of thefrit 80 can range from about 5 to about 100 microns, with the preferredrange in porosity between about 5 and about 50 microns, and morepreferably between about 10 and about 20 microns. Exemplary materialsare porous polymers and cellulose filters.

An open bore 90 is located below the inlet frit 80, which is just belowthe distribution chamber 60. Also below the inlet frit 80 is an upstreamcompression component 85. The illustrated compression component 85 takesthe form of a cylinder surrounding the open central bore 90. Thecompression component 85 is composed of open celled polymeric material,which upon compression exerts a pressure as a result of memory of thematerial. This pressure is measured as a compression deflection (CD) oran indentation load deflection (ILD). In other arrangements, thecompression component can comprise a polymer or metal spring. The bore90 is filled with a core 105 of porous material. The core 105 can betailored as needed, but preferably has a greater porosity in pores perinch (PPI) than the compression component 85.

Below the compression component 85 is an upper reagent restraint 95. Inthe illustrated embodiment, the upper reagent restraint 95 is a disk ofmaterial with a central hole 100 accommodating the core 105. The upperreagent restraint 95 can be porous or nonporous polymeric or cellulosicmaterial. The upper reagent restraint is preferably hydrophilic.

Below the upper reagent restraint 95 is a reagent bed 110. It consistsof a fluid soluble material suitable for administering to a patient viadissolution and IV drip. The core 105 also extends through the reagentbed.

Below the reagent bed 110 is a lower reagent restraint 115. The lowerreagent restraint 115 comprises a pliable or rigid disk. The restraintcan be similar to the upper restraint 95, and is illustrated with alower reagent central hole 120. If pliable, the lower reagent restraint115 is preferably backed by a rigid disk 125, as shown. The lowerreagent restraint 115 is preferably hydrophobic.

The bore 90 thus extends through the compression component 85, the upperreagent restraint 95, the reagent bed 110, the lower reagent restraint115 and (if present) the rigid backing 125.

Below the lower reagent restraint 115 and the rigid backing 125, is acollection area 135. The collection area 135 is defined by the housingbody 37, the lower reagent restraint 115 or the rigid backing 125.

Below the collection area 135 is a terminal frit 140. The terminal frit140 consists of porous polymeric material that may have either ahydrophobic or hydrophilic nature. Preferably, the terminal frit 140 ishydrophobic, such that it generates sufficient back-pressure toaccumulate fluid in the overlying collection area 135 before passing thefluid.

A collection chamber 145 is located below the terminal frit 140. Thecollection chamber 145 is defined by the terminal frit 140, the bottomof the housing 150, and the bottom radial fins 175 located adjacent tothe housing outlet 160. The outlet end of the pack 35 is thus similar tothe inlet end.

The housing outlet 160 forms a tube connecting the housing collectionchamber 145 to the exterior of the housing 37. The exterior terminus ofthe outlet 160 includes a fitting to enable a sterile, closed connectionto the downstream portion of the diluent flow. Both the inlet 40 andoutlet 160 can be covered by port covers (not shown), if desired, tomaintain sterility prior to use.

In operation, with reference to FIG. 2, the drug delivery pack 35 isattached in-line to an intravenous administration set 36 including anupstream reservoir 1 of intravenous fluid connected to a tube 3 linkingthe reservoir to the patient. Attachment of the drug delivery pack 35 isaccomplished by in-line Luer connectors 4 at the inlet and outlet of thedrug delivery pack 35. More specifically, on a preexisting IV line, flowis stopped by closing clips (not shown). The intra-line connections areopened and the drug delivery pack 35 is inserted and locked with Luerlocks. Next, the closing clips on the fluid line are opened and diluentflow is reestablished. It will be readily apparent to those skilled inthe art that a variety of other techniques may be used to connect thedrug delivery pack 35 in-line along an IV line. Such techniques includebut are not limited to having an IV bag spike at the inlet of the drugdelivery pack 35 and/or an IV spike receptacle at the outlet associatedwith a drip chamber.

Referring now to FIG. 3, diluent from the upstream reservoir 1 (FIG. 2)enters the housing 37 via the inlet 40 and first encounters the inletradial fins 65. The inlet radial fins 65 cooperate with back-pressurefrom the inlet frit 80 promote a uniform distribution of diluent acrossthe entire cross-section of the drug delivery pack 35. The downstreamfins 65 similarly cooperate with the outlet frit 140 to form adownstream manifold distribution chambers for the solution. Thehydrophobic nature of the inlet frit 80 forces the diluent to theperiphery within the distribution chamber 60 prior to penetration of thefrit 80. Thus, an initially uniform pattern of diluent flow through theupstream portions of the drug delivery pack 35 is established. It willbe readily apparent to one skilled in the art that other arrangementscan also achieve uniform distribution. Furthermore, the drug pack 35would also entail advantages without an initial uniform distribution.

The uniform face of diluent enters and passes through the uppercompression component 85. After passing through the upper compressioncomponent 85, the diluent encounters the preferred upper reagentrestraint 95 upstream from the reagent bed 110. The hydrophilic natureof the preferred upper reagent restraint 95 thoroughly “wets” therestraint uniformly by capillary action. This serves to provide awetting of the entire reagent bed 110. This is particularly advantageousfor dissolution of hydrophobic reagents.

A portion of the diluent bypasses the reagent bed 110 by traveling downthe porous central core 105 within the bore 90. This diluent accumulatesin the collection area 135 above the hydrophobic terminal frit 140. Thediameter of the bore 90 holding the core 105, together with the relativeporosity and hydrophobocity of the compression component 85, restraint95, reagent bed 110, and restraint 115, determines the portion ofdiluent entering the reagent bed 110, as compared to that bypassing thebed 110. Partitioning the amount of diluent that enters the reagent bed110 effectively regulates the rate of dissolution of that reagent.

Desirably, the hydrophobic nature of the preferred lower reagentrestraint 115 retains diluent with the reagent bed 110, enhancing thewetting of the reagent bed 110. Also, a rigid material may be furnishedto provide support for the reagent restraint 115. Such material mayinclude but is not limited to sintered plastics.

The solution prepared from the dissolving reagent passes through thereagent bed 110 and exits into the central core 105 and/or through thelower restraint 115.

In the upper collection area 135, the portion of the diluent whichbypassed the reagent bed 110 is mixed with the solution formed fromdiluent passing through the reagent bed 110. The solution is thusdiluted within the area 135. Dissolved reagents have time to diffuse toeven out concentration in the preferred embodiment. This is due to thefact that enough solution must gather in the collection area 135 tocreate, preserve and overcome the hydrophobicity of the preferredterminal frit 140. When sufficient solution enters the collection area155 to create sufficient head pressure to overcome the hydrophobicity ofthe terminal frit 140, solution terminal frit 140 and into the lowercollection chamber 145 and into the housing outlet 160. An additionalhydrophobic barrier of varied porosity may also be placed before theoutlet. The collection area 135 can also be created by the use of aspring, rather than the rigid and welded elements 115 or 125, as will beapparent to those skilled in the art.

As will be apparent to the skilled artisan in view of the discussionabove, the various elements in the drug pack 35 can be arranged to varythe relative diluent flow through the core component 105, as compared todiluent flow through the reagent bed 110. Varying the relative flowsthus varies the concentration of drug solution exiting the pack 35. Forexample, for a given set of materials, the diameter of the bore 90 andcore element 105 therein can be varied as desired. Alternatively, for agiven bore 90 size, the relative porosity of the core element 105 ascompared to that of the upper reagent restraint 95 can be changed.Varying materials to accomplish different levels of hydrophobicity canalso influence the relative flow rates. For a given application,accordingly, the skilled artisan can determine an appropriate set ofmaterials and relative dimensions to achieve a desirable solutionconcentration. Thus, no separate diluent line needs to be employed, andthe overall IV administration system is much simplified.

The skilled artisan will readily appreciate, in view of the disclosureherein, numerous other manners of varying the relative flow of diluentsthrough the reagent bed as compared to a bypassing flow. For example, incontrast to the illustrated central core 90 and core element 105 housedtherein, a peripheral gap between the reagent bed 110 and the housing337 can be created by surrounding the bed with a frit having a smallerdiameter than the housing 37, spaced therefrom by periodic spacers orribs, for example. In yet another arrangement, the central core 105 neednot extend through each of the elements 85, 95, 110, 115 and 125. Notethat the inlet frit can also be made hydrophilic to bias fluid flowcoming through the inlet 40, through the central core 105, rather thanencouraging a uniform flow distribution at the inlet end. Such anarrangement would produce a more dilute solution than use of ahydrophobic inlet frit 80.

Preferred Materials

In the preferred embodiment, the inlet frit 80 is polypropylene. Thecompression component 85 is made of an open cell foam. The central core105 is also made of an open cell foam. The terminal frit 140 iscellulose. The lower reagent restraint 115 is hydrophobic and made ofporous polypropylene, to retain diluent within the reagent bed.

The collection area 135 is maintained by a polymer spring with greaterforce deflection than the upper compression component 85, thus spacingthe upper components above the terminal frit 140.

The terminal frit 140 is hydrophobic to form the collection area 135within the housing 37 upstream of the housing outlet.

Exemplary Application

An example of a device for delivery of a typical antibiotic (for examplea cephalosporin like Cefazolin™) with a drug bed 110 of 1000 mg utilizesa housing 37 0.75 inches in internal diameter and a height of 1.25inches. The internal volume of this housing 37 is roughly 9 milliliters.For appropriate delivery this drug is administered over a period of 40minutes, forming a total of 60 milliliters of solution at concentrationbetween 10 and 40 milligrams/milliliter.

The interior of the housing 37 is divided into two chambers. The upperchamber contains the compression component 85, the core and the reagent.For exemplary 1000 mg dose of drug, the dry volume is 3.0 milliliters.The preferred compression component has a height of 0.875 inches. Thecentral cavity 90 within this component 85 has an interior diameter of0.25 inches to accommodate the core 105.

The preferred component 85 has a preferred porosity of about 60 to 90pores per inch (PPI), more preferably 75 PPI, and a preferredcompression load deflection (CLD) of about 0.4 to 0.6 PSI at 25%compression, more preferably 0.5 PSI at this compression. At 65%compression the CLD is preferably about 0.5 to 0.8 PSI, more preferably0.65 PSI. These CLD were determined by measurement of deflection 50square inches of material. It is compressed within the housing to fillthe area upstream of the reagent bed.

The exemplary core 105 has a height of 0.675 inches and an outerdiameter of 0.225 inches. The prosity of this material is preferably 90to 110 PPI, more preferably 100.

The reagent bed restraints 95, 115 have a preferred range in pore sizeof 5 to 25 microns, more preferably about 10 microns. The support forthe reagent bed restraints 95, 115 preferably has pores of 20 to 80microns, more preferably 40 to 60 microns. The diameter of the hole inthe reagent restraints and the support is about 0.215 inches toaccommodate the core 105.

The lower chamber 135 is open with a frit 140 at the distal end of thehousing 37, adjacent to the outlet 160. The frit 140 between the openchamber 135 and the outlet 160 preferably has pores of between 5 and 25microns, more preferably about 10 microns. The frit 140 is preferablyhydrophobic, comprising polypropylene. It has a preferred thickness ofbetween 0.25 and 0.75 inches, more preferably 0.5 inches.

Other variations will be apparent for those skilled in the art. Forinstance, an increased diameter of the housing 37 could be employed withan increased core 105 diameter for hydrophilic reagents to decrease theefficiency of dissolution of the reagent.

What is claimed is:
 1. A drug delivery apparatus comprising: a housinghaving an inlet port, an outlet port, and at least one terminal frit; adrug reagent bed within the housing, the drug reagent bed incommunication with a first fluid flow path between the inlet port andthe outlet, wherein the drug reagent bed comprises reagents for thepreparation of a solution suitable for intravenous administration; and asecond fluid flow path within the housing between the inlet port and theoutlet port, wherein the second fluid flow path bypasses the drugreagent bed.
 2. The apparatus of claim 1, further comprising at leastone compression component positioned to expert pressure on the drugreagent bed.
 3. The apparatus of claim 2, wherein the at least oneterminal frit is hydrophobic.
 4. The apparatus of claim 2, wherein theat least one terminal frit has a porosity from about 5 to 100 microns.5. The apparatus of claim 2, wherein the at least one terminal frit hasa porosity from about 10 to 20 microns.
 6. The apparatus of claim 1,wherein the second fluid flow path is in the middle of the housing. 7.The apparatus of claim 1, wherein a plurality of elements housed withinthe housing are selected to tailor relative flow rates along the firstand second paths to control a concentration of solution formed fromdiluent and the drug reagent bed.
 8. A drug delivery apparatuscomprising: a housing having an inlet port and an outlet port, wherein aplurality of elements housed within the housing are selected to tailorrelative flow rates along the first and second paths to control aconcentration of solution formed from diluent and the drug reagent bed;a drug reagent bed within the housing, the drug reagent bed incommunication with a first fluid flow path between the inlet port andthe outlet; a second fluid flow path within the housing between theinlet port and the outlet port, the second fluid flow path bypassing thedrug reagent bed.
 9. The apparatus of claim 8, further comprising atleast one compression component positioned within the housing to exertpressure on the drug reagent bed.
 10. The apparatus of claim 8, furthercomprising at least one hydrophobic terminal frit.
 11. The apparatus ofclaim 8, wherein the second fluid flow path is in the middle of thehousing.
 12. The apparatus of claim 8, wherein the second fluid flowpath is at the periphery of the housing.
 13. The apparatus of claim 8,wherein the drug reagent bed comprises reagents for the preparation of asolution suitable for intravenous administration.
 14. A drug deliveryapparatus comprising: a housing having an inlet port, an outlet port,and at least one terminal frit, and at least one compression component;a drug reagent bed within the housing, the drug reagent bed incommunication with a first fluid flow path between the inlet port andthe outlet, wherein the drug reagent bed comprises reagents for thepreparation of a solution suitable for intravenous administration, andthe compression component is positioned within the housing to exertpressure on the reagent bed; and a second fluid flow path within thehousing between the inlet port and the outlet port, wherein the secondfluid flow path bypasses the drug reagent bed.
 15. The apparatus ofclaim 14, wherein the at least one terminal frit is an inlet frit. 16.The apparatus of claim 14, wherein the at least one terminal frit is anoutlet frit.
 17. The apparatus of claim 14, wherein the at least oneterminal frit is hydrophobic.
 18. The apparatus of claim 15, wherein theat least one compression component is positioned upstream of the reagentbed.
 19. The apparatus of claim 18, wherein the compression componentcomprises a celled polymeric material.
 20. The apparatus of claim 14,wherein a plurality of elements housed within the housing are selectedto tailor relative flow rates along the first and second paths tocontrol a concentration of solution formed from diluent and the drugreagent bed.